A number of peptide hormones are involved in the control of the different functions in the gastrointestinal (GI) tract, including absorption, secretion, blood flow and motility (Mulvihill, S. J.; et al. in Basic and Clinical Endocrinology, 4th edition, Greenspan, F. S.; Baxter, J. D., Eds., Appleton & Lange: Norwalk, Conn., 1994, pp 551-570). Since interactions between the brain and GI system are critical to the proper modulation of these functions, these peptides can be produced locally in the GI tract or distally in the CNS.
One of these peptide hormones, motilin, a linear 22-amino acid peptide, plays a critical regulatory role in the GI physiological system through governing of fasting gastrointestinal motor activity. As such, the peptide is periodically released from the duodenal mucosa during fasting in mammals, including humans. More precisely, motilin exerts a powerful effect on gastric motility through the contraction of gastrointestinal smooth muscle to stimulate gastric emptying, decrease intestinal transit time and initiate phase III of the migrating motor complex (MMC) in the small bowel. (Itoh, Z., Ed., Motilin, Academic Press: San Diego, Calif., 1990, ASIN: 0123757304; Itoh, Z. Peptides 1997, 18, 593-608; Nelson, D. K. Dig. Dis. Sci. 1996, 41, 2006-2015; Peeters, T. L.; Vantrappen, G.; Janssens, J. Gastroenterology 1980, 79, 716-719; Itoh, Z.; Sekiguchi, T. Scand. J. Gastroenterol. Suppl. 1983, 82, 121-134; Itoh, Z.; Aizawa, I.; Sekiguchi, T. Clin. Gastroenterol. 1982, 11, 497-521; Luiking, Y. C.; Peeters, T. L.; Stolk, M. F.; Nieuwenhuijs, V. B.; Portincasa, P.; Depoortere, I.; Van Berge Henegouwen, G. P.; Akkermans, L. M. A. Gut 1998, 42, 830-835.)
Motilin can exert these effects through receptors located predominantly on the human antrum and proximal duodenum, although its receptors are found to some degree along the entire GI tract. (Peeters, T. L.; Bormans, V.; Vantrappen, G. Regul. Pept. 1988, 23, 171-182; Poitras, P.; Miller, P.; Dickner, M.; Mao, Y. K.; Daniel, E. E.; St-Pierre, S.; Trudel, L. Peptides 1996, 17, 701-707; Miller, P.; Trudel, L.; St-Pierre, S.; Takanashi, H.; Poitras, P. Peptides 2000, 21, 283-287; Takeshita E, Matsuura B, Dong M, Miller L J, Matsui H, Onji M. J. Gastroenterol. 2006, 41, 223-230.) Therefore, motilin hormone is involved in motility of both the upper and lower parts of the GI system. In addition, motilin and its receptors have been found in the CNS and periphery, suggesting a physiological role in the nervous system that has not yet been definitively elucidated. (Peeters, T. L.; Tang, M. Peptides 2007, 28, 625-631; Liu, M.; Dong, L.; Duan, Z.; Zhu, W.-y.; Cui, Y.; Lei, L. J. Med. Colleges PLA 2005, 20, 321-326; Thielemans, L.; Depoortere, I.; Van Assche, G.; Bender, E.; Peeters, T. L. Brain Res. 2001, 895, 119-128; Depoortere, I.; Peeters, T. L. Am. J. Physiol. 1997, 272, G994-G999 and O'Donohue, T. L.; et al. Peptides 1981, 2, 467-477.) Recently, motilin receptors were found to be expressed in Purkinje cells of both human and rat cerebellum. (Chen, H.; Chen, L.; Wang, J. J.; Wei, H. J.; Yung, W. H. NeuroReport 2007, 18, 1345-1349.) Motilin receptors in the brain have been suggested to play a regulatory role in a number of CNS functions, including feeding and drinking behavior, micturition reflex, central and brain stem neuronal modulation, and pituitary hormone secretion (Itoh, Z. Peptides 1997, 18, 593-608; Asakawa, A.; Inui, A.; Momose, K. M.; et al. Peptides 1998, 19, 987-990 and Rosenfeld, D. J.; Garthwaite, T. L. Physiol. Behav. 1987, 39, 753-756). Studies in infants have also indicated a role for motilin in the long-term regulation of energy balance. (Savino, R.; Grassino, E. C.; Fissore, M. F.; et al. Clin. Endocrinol. 2006, 65, 158-162.)
The recent identification and cloning of the human motilin receptor (Intl. Pat. Appl. Publ. WO 99/64436; Feighner, S. D.; Tan, C. P.; McKee, K. K.; et al. Science 1999; 284, 2184-2188) has simplified and accelerated the search for agents which can modulate its activity for specific therapeutic purposes. Due to the involvement of motilin in control of gastric motility, agents that either diminish (in the case of hypermotility disorders) or enhance (in the case of hypomotility disorders) the activity at the motilin receptor are a particularly attractive area for further investigation in the search for new effective pharmaceuticals towards a number of GI indications. (Besterman, H. S. J. Clin. Pathol. Suppl. 1978, 8, 76-84; Tack, J. Basic Pract. Res. Clin. Gastroenterol. 2007, 21, 633-644.)
Two primary avenues have been pursued to discover and develop motilin agonists as therapeutic agents to enhance motility. (Peeters, T. L. Neurogastroenterol. Motil. 2006; 18, 1-5; Sandham, D. A.; Plannkuche, H.-J. Ann. Rep. Med. Chem. 2006, 41, 211-219.) The first of these, peptidic agonists of the motilin receptor, have clinical application for the treatment of hypomotility disorders, in particular gastroparesis, (Haramura, M.; Tsuzuki, K.; Okamachi, A.; et al. Bioorg. Med. Chem. 2002, 10, 1805-1811; U.S. Pat. Nos. 5,422,341; 5,432,261; 5,459,049; 5,695,952; 5,721,353; 5,734,012; 6,018,037; 6,380,158; 6,420,521, 6,838,438; U.S. Pat. Appl. Publ. 2001/041791; 2003/176640; 2004/254345; 2005/065156; 2005/080116, 2005/106146; 2005/208626; Intl. Pat. Appl. Publ. WO 98/42840; WO 01/00830; WO 02/059141). Structure-activity studies have determined the key residues in the native peptide (Peeters, T. L.; Macielag, M. J.; Depoortere, I.; et al. Peptides 1992, 13, 1103-1107; Haramura, M.; Tsuzuki, K.; Okamachi, A.; et al. Chem. Pharm. Bull. 1999, 47, 1555-1559) and NMR studies have defined its solution structure (Massad, T.; Jarvet, J.; Taner, R.; et al. J. Biomol. NMR 2007, 38, 107-123). In addition, studies on the motilin receptor and on the interaction of peptide and non-peptide agonists with the motilin receptor have delineated differential contributions of the receptor extracellular domains to binding. (Matsuura, B.; Dong, M.; Miller, L. J. J. Biol. Chem. 2002, 277, 9834-9839; Matsuura, B.; Dong, M.; Naik, S.; Miller, L. J.; Onji, M. J. Biol. Chem. 2006, 281, 12390-12396.) Atilmotin, a peptide analogue derived from the C-terminal 14 residues of motilin, has shown promising results in early human studies. (Park, M. I.; Ferber, I.; Camilleri, M.; et al. Neurogastroenterol. Motil. 2006, 18, 28-36; Intl. Pat. Appl. Publ. WO 2006/138023; WO 2006/138026; U.S. Pat. Appl. Publ. 2006/287243; 2006/293243.)
The macrolide antibiotic erythromycin has long been known to have stimulation of GI motility as a side effect and, hence, has been utilized as a treatment for gastroparesis. This effect has subsequently been shown to be mediated through interaction at the motilin receptor. (Hasler, W. L.; Heldsinger, A.; Chungal, O. Y. Am. J. Physiol. 1992, 262, G50-G55; Peeters, T. L. Gastroenterology 1993, 105, 1886-1899; Weber, F. H., Jr.; Richards, R. D.; McCallum, R. W. Am. J. Gastroenterol. 1993, 88, 485-490.) However, use of erythromycin therapy can be associated with nausea, diarrhea, cramping and abdominal pain and, further, must be limited in duration to avoid development of bacterial resistance. Therefore, as the second major strategy aimed at motilin agonist therapeutics, the development of derivatives of erythromycin (commonly referred to as motilides) which have little or no antibiotic activity, yet maintain the GI stimulatory effects, has been the subject of a considerable number of research efforts. (Faghih, R.; Nellans, H. N.; Plattner, J. J. Drugs of the Future 1998, 23, 861-872; Salat, P.; Parikh, V. Ind. J. Pharmacol. 1999, 31, 333-339; Wu, Y. J. Curr. Pharm. Des. 2000, 6, 181-223; Inatomi, N.; Sato, F.; Itoh, Z.; Omura, S. Mode of action of macrolides with motilin agonistic activity-motilides. Macrolide Antibiotics, 2nd edition, Omura, S., ed., Academic Press: San Diego, Calif., 2002, pp 501-531; U.S. Pat. Nos. 4,677,097; 4,920,102; 5,008,249; 5,175,150; 5,418,224; 5,470,961; 5,523,401; 5,523,418; 5,538,961; 5,554,605; 5,578,579; 5,658,888; 5,712,253; 5,854,407; 5,912,235; 5,922,849; 6,077,943; 6,084,079; 6,100,239; 6,165,985; 6,403,775; 6,562,795; 6,750,205; 6,939,861; 6,946,482; 7,211,568; U.S. Pat. Appl. Publ. 2002/025936; 2002/094962; 2003/220271; 2004/138150; 2004/147461; 2005/119195; 2006/270616; Intl. Pat. Appl. Publ. WO 01/60833; WO 02/051855; WO 2004/19879; WO 2005/18576; WO 2006/070937; WO 2006/127252.) Generally disappointing results in clinical trials have been observed for such motilides as EM-574 (Satoh, M.; Sakai, T.; Sano, I.; et al. J. Pharmacol. Exp. Ther. 1994, 271, 574-579; Choi, M. G.; Camilleri, M.; Burton, D. D.; Johnson, S.; Edmonds, A. J. Pharmacol. Exp. Ther. 1998, 285, 37-40), ABT-229 (alemcinal, Talley, N. J.; Verlinden, M.; Snape, W.; et al. Aliment. Pharmacol. Ther. 2000, 14, 1653-1661; Talley, N. J.; Verlinden, M.; Geenan, D. J.; et al. Gut 2001, 49, 395-401; Chen, C. L.; Orr, W. C.; Verlinden, M. H.; et al. Aliment. Pharmacol. Ther. 2002, 16, 749-757; Netzer, P.; Schmitt, B.; Inauen, W. Aliment. Pharmacol. Ther. 2002, 16, 1481-1490) and GM-611 (mitemcinal, Peeters, T. L. Curr. Opin. Investig. Drugs. 2001, 2, 555-557; Koga, H.; Takanashi, H.; Itoh, Z.; Omura, S. Drugs of the Future 2002, 27, 255-272; Takanashi, H.; Yogo, K.; Ozaki, K.; Koga, H.; Itoh, Z.; Omura, S. Pharmacology 2007, 79, 137-148; Ozaki, K. I.; Yogo, K.; Sudo, H.; Onoma, M.; Kamei, K.; Akima, M.; Koga, H.; Itoh, Z.; Omura, S.; Takanashi, H. Pharmacology 2007, 79, 223-235; Ozaki, K.; Sudo, H.; Muramatsu, H.; Yogo, K.; Kamei, K.; Koga, H.; Itoh, Z.; Omura, S.; Takanashi, H. Inflammopharmacology 2007, 15, 36-42; McCallum, R. W.; Cynshi, O. Aliment. Pharmacol. Ther. 2007, 26, 107-116), primarily due to issues such as poor bioavailability, chemical instability and tachyphylaxis. (Thielemans, L.; Depoortere, I.; Perret, J.; et al. J. Pharmacol. Exp. Ther. 2005, 313, 1397-1405; Mitselos, A.; Depoortere, I.; Peeters, T. L. Biochem. Pharmacol. 2007, 73, 115-124.) Nonetheless, due to the therapeutic potential of such agents, the search for motilin agonists in this class has continued and, recently, KOS-2187 (Carreras, C. W.; Liu, Y.; Chen, Y.; et al. Gastroenterology 2005, 128, A464; Carreras, C. W.; Burlingame, M.; Carney, J.; et al. Can. J. Gastroenterol. 2005, 19, 15) has been described and appears to circumvent many of these problems. A method useful for analyzing the therapeutic efficiency of these types of molecules has also been formulated (U.S. Pat. No. 6,875,576; U.S. Pat. Appl. Publ. 2002/192709; Intl. Pat. Appl. Publ. WO 02/64092).
Similarly, non-peptide, non-motilide motilin agonists have been reported (U.S. Pat. No. 7,262,195; U.S. Pat. Appl. Publ. No. 2004/152732; 2005/065156; Intl. Pat. Appl. Publ. WO 02/137127; WO 02/92592; WO 2005/027908; WO 2005/027637; Jap. Pat. Abstr. Publ. No. 09249620). Of these, BMS-591348 has been described as possessing a pharmacological profile that avoids the tachyphylaxis issues that plagued many of the previous motilin agonist efforts. (Li, J. J.; Chao, H. G.; Wang, H.; et al. J. Med. Chem. 2004, 47, 1704-1708; Lamian, V.; Rich, A.; Ma, Z.; Li, J. Seethala, R.; Gordon, D.; Dubaquie, Y. Mol. Pharmacol. 2006, 69, 109-118.)
On the other hand, antagonists of the motilin receptor are potentially useful as therapeutic treatments for diseases associated with hypermotilinemia and/or gastrointestinal hypermotility, including diarrhea, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease, other types of diarrhea, dyspepsia, irritable bowel syndrome, functional gastrointestinal disorders, chemotherapy-induced nausea and vomiting (emesis) and post-operative nausea and vomiting. Current treatments for these conditions are ineffective in many cases. Loperamide, an opioid agonist, is useful for milder diarrhea and generally does not work in a high percentage of patients. Octreotide, a somatostatin agonist, is used off-label as a diarrheal treatment, but is relatively expensive, given by injection, and also not effective in many instances. Further, motilin levels have been observed to be elevated in patients with acute diarrhea (Besterman, H. S.; Christofides, N. D.; Welsby, P. D.; et al. Gut 1983, 24, 665-671) and traveler's diarrhea (Besterman, H. S.; Cook, G. C.; Sarson, D. L.; et al. Br. Med. J. 1979, 17, 1252-1255).
Diarrhea is a common and serious side-effect experienced by cancer patients resulting from surgery, bone marrow transplantation, chemotherapy and radiation treatment. (Stern, J.; Ippoliti, C. Sem. Oncol. Nurs. 2003, 19, 11-16; Benson, A. B., III; Ajani, J. A.; Catalano, R. B.; et al. J. Clin. Oncol. 2004, 22, 2918-2926; O'Brien, B. E.; Kaklamani, V. G.; Benson, A. B. III Clin. Colorectal Canc. 2005, 4, 375-381.) Certain chemotherapeutic regimens, particularly those including fluoropyrimidines and irinotecan, result in chemotherapy-induced diarrhea (CID) rates as high as 50-80%. (Arbuckle, R. B.; Huber, S. L.; Zacker, C. The Oncologist 2000, 5, 250-259; Saltz, L. B. J. Support. Oncol. 2003, 1, 35-46; Goldberg-Arnold, R. J.; Gabrail, N.; Raut, M.; Kim, R.; Sung, J. C. Y.; Zhou, Y. J. Support. Oncol. 2005, 3, 227-232; Sharma, R.; Tobin, P.; Clarke, S. J. Lancet Oncol. 2005, 6, 93-102; Gibson, R. J.; Keefe, D. M. K. Support. Care Cancer 2006, 14, 890-900.) The implications of CID include increased morbidity and mortality. This presents a significant problem as, in 2001, over 1.4 million individuals in the U.S. were undergoing cancer chemotherapy. A large heterogeneous study of cancer patients at all stages of treatment placed the prevalence of diarrhea at 14%. (M. D. Anderson Symptom Inventory, Cancer 2000, 89(7), 1634-1646). However, for certain types of cancer, the occurrence is higher. In colorectal cancer, for example, more than half of patients experienced diarrhea rated serious (grade 3) or higher. Resulting from tissue damage in the intestine caused by drugs designed to thwart the rapid growth of tumor cells, it also affects the cells lining the intestinal wall. No effective therapy exists for this damage nor for the associated diarrhea.
In general, from 10-20% of patients experience CID, although for some chemotherapeutic agents the incidence can be as high as 90%. In approximately 20% of patients, the adverse effects are so severe, it requires a halt to or reduction of the treatment regimen and, often, hospitalization. In addition, parenteral nutrition often must be taken due to the inability of patients to take nourishment normally. Hence, this has an effect on the efficacy of the chemotherapy. Indeed, a review of clinical trials in colorectal cancer revealed higher death rates primarily due to gastrointestinal toxicity. (Rothenberg, M. L.; Meropol, N. J.; Poplin, E. A.; VanCutsem, E.; Wadler, S. J. Clin. Oncol. 2001, 19, 3801-3807.) Current pharmacological treatments only work in some patients and are much less effective against the more serious grades of diarrhea. (MacNaughton, W. K. Aliment. Pharmacol. Ther. 2000, 14, 523-528).
Acute radiation enteritis (ARE) or radiation induced intestinal dysfunction occurs in 75% of patients undergoing radiation therapy, typically occurring in the second or third week of therapy. Characterized by abdominal cramping and diarrhea, this is a serious and feared side effect that results in increased overall treatment time as well as reduced quality of life and can even result in death. In 5-15% of patients, the condition becomes chronic. In addition to discomfort, this side effect decreases the therapeutic benefit from radiation treatment by increasing the overall treatment time. (MacNaughton, W. K. Aliment. Pharmacol. Ther. 2000, 14, 523-528; Nguyen, N. P.; Antoine, J. E.; Dutta, S.; Karlsson, U.; Sallah, S. Cancer 2002, 95, 1151-1163; Gwede, C. K. Sem. Nursing Oncol. 2003, 19, 6-10.)
Indeed, chronic diarrhea can arise as a result of numerous medical conditions. (Schiller, L. R. Curr. Treat. Options Gastroenterol. 2005, 8, 259-266; Spiller, R. Neurogastroenterol. Motil. 2006, 18, 1045-1055.) For example, chronic diarrhea is a common problem for patients with human immunodeficiency virus infection, especially those with advanced disease. This is a debilitating side effect that occurs in 60-90% of AIDS patients. (Cohen, J.; West, A. B.; Bini, E. J. Gastroenterol. Clin. North Am. 2001, 30, 637-664; Oldfield, E. C., III Rev. Gastroenterol. Disord. 2002, 2, 176-88; Sestak, K.; Curr. HIV Res. 2005, 3, 199-205; Thom, K.; Forrest, G. Curr. Opin. Gastroenterol. 2006, 22, 18-23.) Additionally, psychological factors, such as stress, are known to play a role in adversely affecting the proper functioning of the GI tract. (North, C. S.; Alpers, D. H.; Thompson, S. J.; Spitznagel, E. L. Dig. Dis. Sci. 1996, 41, 633-640; Kamm, M. A. Eur. J. Surg. Suppl. 1998, 583, 37-40; Botha, C.; Libby, G. Br. J. Hosp. Med. (Lond.) 2006, 67, 344-349.)
Traveller's diarrhea affects over 50% of travellers to some destinations, particularly tropical ones, and is estimated to afflict over 11 million individuals annually. Apart from the disruption to business, travel and vacation schedules, this condition is often accompanied by other clinical manifestations such as nausea, vomiting, abdominal pain, fecal urgency, bloody stools, and fever. (Lima, A. A. M. Curr. Opin. Infect. Dis. 2001, 14, 547-552; Al-Abri, S. S.; Beeching, N. J.; Nye, F. J. Lancet Infect. Dis. 2005, 5, 349-360; DuPont, H. L. Gastroenterol. Clin. North Am. 2006, 35, 337-353.)
Clostridium difficile is the etiological agent responsible for about one-third of cases of antibiotic-associated diarrhea and is estimated to cause a $1 billion annual cost in the U.S. Antibiotic-associated diarrhea is more common in the hospital setting with up to 29% of patients developing the condition, resulting in increased length of stay, increased cost of care, and increased mortality. (Bartlett, J. G. N. Engl. J. Med. 2002, 346, 334-339; Kelly, C. P.; Pothoulakis, C.; LaMont, J. T. N. Engl. J. Med. 1994, 330, 257-262; Kyne, L.; Farrell, R. J.; Kelly, C. P. Gastroenterol. Clin. N. Am. 2001, 30, 753-777; Malnick, S. D. H.; Zimhony, O. Ann. Pharmacother. 2002, 36, 1767-1775; Hull, M. W.; Beck, P. L. Can. Fam. Phys. 2004, 50, 1536-1540; Schroeder, M. S. Am. Fam. Phys. 2005, 71, 921-928; Voth, D. E.; Ballard, J. D. Clin. Microbiol. Rev. 2005, 18, 247-263.) It is a serious condition with a mortality rate as high as 25% in frail elderly patients. Recently, the incidence and severity of C. difficile-associated diarrhea (CADD) has begun to increase dramatically. (Frost. F.; Craun, G. F.; Calderon, R. L. Emerg. Infect. Dis. 1998, 4, 619-625; Olfield, E. C. Rev. Gastroenterol. Disord. 2006, 6, 79-96.)
Diarrhea is also induced in patients with graft versus host disease (GVHD). GVHD is a common, potentially life-threatening complication of allogenic hematopoietic stem cell transplantation. Gastrointestinal GVHD frequently involves the colon and complicates management of these seriously ill patients. (Flowers, M. E.; Kansu, E.; Sullivan, K. M. Hematol Oncol Clin North Am. 1999, 13, 1091-1112; Ross, W. A.; Couriel, D. Curr. Opin. Gastroenterol. 2005, 21, 64-69.) In addition, diarrhea is a common side effect after other types of transplantation with an incidence ranging from 10% to 43%. Diarrhea is also a frequent side effect of immunosuppressive medications. (Ginsburg, P. M.; Thuluvath, P. J. Liver Transpl. 2005, 11, 881-890.)
Irritable bowel syndrome (IBS) is the most common functional GI disorder with an estimated worldwide prevalence of 10-15%. (Saito, Y. A.; Schoenfeld, P.; Locke, G. R. Am. J. Gastroenterol. 2002, 97, 1910-1915; Gilkin, R. J., Jr. Clin. Ther. 2005, 27, 1696-1709; Lacy, B. E.; De Lee, R. J. Clin. Gastroenterol. 2005, 39, S230-S242; Talley, N. J. Intern. Med. J. 2006, 36, 724-728; Ohman, L.; Simren, M. Dig. Liver Dis. 2007, 39, 201-215.) The total annual cost attributable to IBS is estimated to be $30 billion, including $10 billion in direct costs from physician visits and prescription pharmaceuticals, as well as a significant cost from missed work days. (Talley, N. J.; Gabriel, S. E.; Harmsen, W. S.; et al. Gastroenterology 1995, 109, 1736-1741; Maxion-Bergemann, S.; Thielecke, F.; Abel, F.; Bergemann, R. Pharmacoeconomics 2006, 24, 21-37.) IBS patients are sub-classified into diarrhea-predominant (IBS-d), constipation-predominant (IBS-c) or those alternating between these two patterns (IBS-m). Treatments for these various subsets generally must be approached with separate and specific therapies. Antispasmodics, tricyclic antidepressants, selective serotonin reuptake inhibitors, laxatives, antidiarrheals, and bulking agents have not proven to be widely effective and tend to treat symptoms, rather than underlying pathophysiology. (Schoenfeld, P. Gastroenterol. Clin. North Am. 2005, 34, 319-335; Cremonini, F.; Talley, N. J. Nat. Clin. Pract. Gastroenterol. Hepatol. 2005, 2, 82-88; Andersen, V.; Camilleri, M. Drugs 2006, 66, 1073-1088.) The plasma levels of motilin have been shown to be elevated in patients with IBS. (Simren, M.; Bjornsson, E. S.; Abrahamsson, H. Neurogastroenterol. Motil. 2005, 17, 51-57.) Motilin antagonists, hence, would be a useful treatment for patients with IBS. They would likely be more suited to IBS-d and to a lesser extent, IBS-m. IBS-d is manifested by fecal urgency and frequent loose bowel movements (>3 per day). Individuals suffering from IBS-d account, for approximately one-third of the entire IBS patient population.
Another extremely common GI disorder, dyspepsia, is characterized by chronic or recurrent upper GI distress with no obvious physical cause: (Tack, J.; Bisschops, R.; Sarnelli, G. Gastroenterology 2004, 127, 1239-1255; Kleibeuker, J. H.; Thijs, J. C. Curr. Opin. Gastroenterol. 2004, 20, 546-550; Talley, N. J.; Vakil, N.; et al. Am. J. Gastroenterol. 2005, 100, 2324-2337; Talley, N. J.; Vakil, N.; Moayyedi, P. Gastroenterology 2005, 129, 1756-1780; Smith, M. L. Dig. Liver Dis. 2005, 37, 547-558; Saad, R. J.; Chey, W. D. Aliment. Pharmacol. Ther. 2006, 24, 475-492; Suzuki, H.; Nishizawa, T.; Hibi, T. J. Gastroenterol. 2006, 41, 513-523.; Mahadeva, S.; Goh, K. L. World J. Gastroenterol. 2006, 12, 2661-2666; Monkemuller K, Malfertheiner P. World J. Gastroenterol. 2006, 12, 2694-2700; Mizuta, Y.; Shikuwa, S.; Isomoto, H.; Mishima, R.; Akazawa, Y.; Masuda, J.; Omagari, K.; Takeshima, F.; Kohno, S. J. Gastroenterol. 2006; 41, 1025-1040; Chua, A. S. World J. Gastroenterol. 2006, 12, 2656-2659.) Typical symptoms include gastric fullness, bloating, pain, nausea and vomiting. This disease has prevalence as high as 20% annually in Western countries. It accounts for up to 5% of all visits to primary care physicians and 30% of visits to GI specialists. As with IBS, the patient population can be categorized into various subsets based upon symptoms. (Choung, R. S.; Locke, G. R. III; Schleck, C. D.; Zinsmetister, A. R.; Talley, N. J. Am. J. Gastroenterol. 2007, 102, 1983-1989.) However, the largest patient subset (up to 60%) suffers from dyspepsia with no known organic cause, otherwise known as “functional dyspepsia (FD).” FD has a major impact on quality of life and health care resources. In analogy with IBS, no widely-accepted therapy for the treatment of FD currently exists. (Stanghellini, V.; De Ponti, F.; De Giorgio, R.; et al. Drugs 2003, 63, 869-892; Cremonini, F.; Delgado-Aros, S.; Talley, N. J. Best Pract. Res. Clin. Gastroenterol. 2004, 18, 717-733; McNally, M. A.; Talley, N. J. Curr. Treatment Opt. Gastroenterol. 2007, 10, 157-168.) Circulating plasma motilin levels are also seen to be raised in patients suffering from dyspepsia. (Kusano, M.; Sekiguchi, T.; Kawamura, O.; Kikuchi, K.; Miyazaki, M.; Tsunoda, T.; Horikoshi, T.; Mori, M. Am. J. Gastroenterol. 1997, 92, 481-484; Kamerling, I. M.; Van Haarst, A. D.; Burggraaf, J.; Schoemaker, R. C.; Biemond, I.; Heinzerling, H.; Jones, R.; Cohen, A. F.; Masclee, A. A. Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 284, G776-G781.) As with IBS, motilin antagonists would mitigate the effects of motilin in such patients.
Chemotherapy-induced nausea and vomiting (CINV), or emesis, is one of the most severe adverse effects resulting from cancer treatment and is often cited as the side effect most feared by patients. From 70-80% of patients receiving cancer chemotherapy experience CINV. In addition to a significant deterioration in quality of life, this condition often requires modification or delay of chemotherapeutic regimens with concomitant negative impact on the effectiveness of treatment. Despite recent progress in the development and availability of new approaches to mitigating the effects of CINV, there remains a compelling need for alternative strategies for patients for whom current treatments are inadequate. (Lindley, C. M.; Hirsch, J. D.; O'Neill, C. V.; Transau, M. D.; Gilbert, C. S.; Osterhaus, J. T. Qual. Life Res. 1992, 1, 331-340; Martin, M. Oncology 1996, 53, 26-31; Kovac, A. L. Drug Safety 2003, 26, 227-259; Grunberg, S. M. J. Support. Oncol. 2004, 2, 1-12; Jordan, K.; Kasper, C.; Schmoll, H.-J. Eur. J. Canc. 2005, 41, 199-205; Herrstedt, J.; Dombernowsky, P. Basic Clin. Pharmacol. Toxicol. 2007, 101, 143-150.)
Post-operative nausea and vomiting (PONV) is a common complication from surgery, occurring in 30-50% of patients. PONV can lead to unintended or extended hospitalization, electrolyte abnormalities and strain on surgical sutures, plus a substantial negative effect on quality of life. As such, it increases health care costs and decreases patient satisfaction. The importance of dealing with PONV has become well-recognized in the medical community and there is a need for effective treatments. (Osoba, D.; Zee, B.; Warr, D.; et al. Support. Care Cancer 1997, 5, 303-313; Kovac, A. L. Drugs 2000, 59, 213-243; Gan, T. J. J. Am. Med. Assoc. 2002, 287, 1233-1236; Tramèr, M. R. Best Pract. Res. Clin. Anaesthesiol. 2004, 18, 693-701; Habib, A. S.; Gan, T. J. Can. J. Anesth. 2004, 51, 326-341; Golembiewski, J.; Chernin, E.; Chopra, T. Am. J. Health-Syst. Pharm. 2005, 62, 1247-1260.)
In addition to its actions on motility, motilin is involved in inducing secretion within the gastrointestinal tract. Motilin plays a role in gastric and pancreatic secretion in dogs. (Konturek, S. J.; Dembinski, A.; Krol, R.; Wunsch, E. Scand. J. Gastroenterol. 1976, 11, 57-61; Magee, D. F.; Naruse, S. J. Physiol. 1984, 355, 441-447; Lee, K. L.; Shiratori, K.; Chen, Y. F.; Chang, T.-M.; Chey, W. Y. Am. J. Physiol. 1986, 14, G759-764.) Similarly, intestinal secretagogue activity in humans has been described for [Nle13]-motilin. (Kachel, G. W.; Frase, L. L.; Domschke, W.; Chey, W. Y.; Krejs, G. J. Gastroenterology 1984, 87, 550-556.) Hence, an antagonist of the motilin receptor may show anti-secretory effects and play a role as an anti-diarrheal agent. Anti-secretory agents have proven to be effective anti-diarrheal therapeutics. (Farthing, M. J. G. Exp. Opin. Invest. Drugs 2004, 13, 777-785; Farthing, M. J. G. Dig. Dis. 2006, 24, 47-58.) This dual role, as both an anti-motility and an anti-secretory agent would make motilin antagonists even more effective therapeutics for the treatment of diarrheal conditions.
In addition to treatment of disorders characterized by hypermotility, the use of motilin antagonists would also be useful in the treatment of diseases and disorders characterized by poor stomach or intestinal absorption. A motilin antagonist would slow gastrointestinal motility thereby permitting longer GI exposure time for absorption of necessary nutrients. Such diseases and disorders include celiac disease, a chronic disorder afflicting almost 1% of the population. Celiac disease is a GI disorder characterized by inflammation, leading to injury to the mucosal lining of the small intestine. The inflammation results when gliadin, a protein found in gluten-containing foods, is ingested by genetically susceptible individuals. The mucosal damage and subsequent malabsorption of nutrients can lead to numerous complications. (Alaedini, A.; Green, P. H. R. Ann. Intern. Med. 2005, 142, 289-298; Koning, F. Gastroenterology 2005, 129, 1294-1301; Chand, N.; Mihas, A. A. J. Clin. Gastroenterol. 2006, 40, 3-14; Westerberg, D. P.; Gill, J. M.; Dave, B.; et al. J. Am. Osteopath. Assn. 2006, 106, 145-151; Jones, R. B.; Robins, G. G.; Howdle, P. D. Curr. Opin. Gastroenterol. 2006, 22, 117-123; Green, P. H. R.; Jabri, B. Ann. Rev. Med. 2006, 57, 207-221; Hill, I. D. Curr. Treat. Options Gastroenterol. 2006, 9, 399-408.) The only current treatment is modification to a gluten-free diet.
Short bowel syndrome is a medical condition that occurs after resection of a substantial portion of small intestine and is characterized by malnutrition. (Misiakos, E. P.; Macheras, A.; Kapetanakis, T.; Liakakos, T. J. Clin. Gastroenterol. 2007, 41, 5-18.; Buchman, A. L. Gastroenterology. 2006, 130 (Suppl. 1), S5-S15; Jackson, C.; Buchman, A. L. Curr. Gastroenterol. Rep. 2005, 7, 373-378; Scolapio, J. S. Curr. Opin. Gastroenterol. 2004, 20, 143-145; Buchman, A. L.; Scolapio, J.; Fryer, J. Gastroenterology 2003, 124, 1111-1134; Westergaard, H. Sem. Gastrointest. Dis. 2002, 13, 210-220.) The syndrome is particularly distressing in children, where mortality and morbidity are very high. (Vanderhoof, J. A.; Young, R. J.; Thompson, J. S. Pediatric Drugs 2003, 5, 625-631; Vanderhoof, J. A. J. Ped. Gastroenterol. Nutri. 2004, 39, 5768-5771; Sukhotnik, I.; Coran, A. G.; et al. Pediatr. Surg. Int. 2005, 21, 947-953.) No current pharmacological agents are currently approved for SBS, which is typically treated through intestinal adaptation or rehabilitation in order to improve nutritional status of SBS patients. (DiBaise, J. K.; Young, R. J.; Vanderhoof, J. A. Am. J. Gastroenterol. 2004, 99, 1823-1832.)
Additionally, the potential for improving nutrient absorption through the use of motilin antagonists could be useful in the treatment of cachexia, a wasting disorder common in serious illnesses such as cancer, AIDS, chronic heart failure and other cardiovascular diseases, and renal disease, as well as in the aged. Cancer cachexia is a therapeutic condition characterized by weight loss and muscle wasting and afflicts approximately 50% of all cancer patients and is the main cause of death in more than 20% of patients. Additionally, this condition has been shown to be a strong independent risk factor for mortality. (Kern, K. A.; Norton, J. A. JPEN 1980, 12, 286-298; Tisdale, M. J. J. Natl. Cancer Inst. 1997, 89, 1763-1773; Gagnon, B.; Bruera, E. Drugs 1998, 55, 675-688; Inui, A. CA Cancer J. Clin. 2002, 52, 72-91.) Likewise, patients suffering from chronic heart failure are at serious risk from a similar wasting syndrome. (Springer, J.; Filippatos, G.; Akashi, Y. J.; Anker, S. D. Curr. Opin. Cardiol. 2006, 21, 229-233; Akashi, Y. J.; Springer, J.; Anker, S. D. Curr. Heart Fail. Rep. 2005, 2, 198-203; Anker, S. D.; Steinborn, W.; Strassburg, S. Ann. Med. 2004, 36, 518-529.) This condition also affects an increasing proportion of the elderly. (Morley, J. E. J. Gerontology, Ser. A: Biol. Sci. Med. Sci. 2003, 58A, 131-137.)
Additionally, the association between intestinal inflammation and altered intestinal motility is well-established. Further, motilin has been implicated in inflammatory disorders of the GI system. Elevated motilin levels have been observed in patients with inflammatory bowel disease (Besterman, H. S.; Mallinson, C. N.; et al. Scand. J. Gastroenterol. 1983, 18, 845-852), ulcerative colitis (Greenberg, G. R.; Buchan, A. M.; McLeod, R. S.; Preston, P.; Cohen, Z. Gut 1989, 30, 1721-1730) and chronic pancreatitis (Besterman, H. S.; Adrian, T. E.; Bloom, S. R. et al. Digestion 1982, 24, 195-208). In addition, increased motilin and mRNA expression have been found in a rabbit colitis model (Depoortere, I.; Van Assche, G.; Peeters, T. L. Neurogastroenterol. Motil. 2001, 13, 55-63.) Increased plasma motilin concentrations were also obtained in patients after intestinal resection (Besterman, H. S.; Adrian, T. E.; Mallinson, C. N. Gut 1982, 23, 854-861) and ileostomy (Kennedy, H. J.; Sarson, D. L.; Bloom, S. R.; et al. Digestion 1982, 24, 133-136). It has further been shown that non-steriodal anti-inflammatory drugs can induce hypermolitinemia, disturb the interdigestive migrating motor complex, and contribute to the formation of gastric ulcers. (Narita, T.; Okabe, N.; Hane, M.; et al. J. Vet. Pharmacol. Ther. 2006, 29, 569-577.) Therefore, motilin antagonists may be used as anti-inflammatory agents, in particular for use in the GI tract, with beneficial properties relative to existing treatments.
Despite the potential offered by motilin antagonists as a novel approach to treat hypermotility and malabsorption disorders, efforts have lagged those directed at agonists. A variety of peptidic compounds have been described as antagonists of the motilin receptor [(ANQ-11125: Peeters, T. L.; Depoortere, I.; Macielag, M. J.; Marvin, M. S.; Florance, J. R.; Galdes, A. Biochem. Biophys. Res. Comm. 1994, 198, 411-416); (OHM-11526: Farrugia, G.; Macielag, M. J.; Peeters, T. L.; San, M. G.; Galdes, A.; Szurszewski, J. H. Am. J. Physiol. 1997, 273, G404-G412; Depoortere, I.; Macielag, M. J.; Galdes, A.; Peeters, T. L. Eur. J. Pharmacol. 1995, 286, 241-247); (MA-2029: Mitselos, A.; Depoortere, I.; Peeters, T. L. Biochem. Pharmacol. 2007, 73, 115-124); Poitras, P.; Miller, P.; Gagnon, D.; St-Pierre, S. Biochem. Biophys. Res. Comm. 1994, 205, 449-454; U.S. Pat. Nos. 5,470,830; 6,255,285; 6,586,630; 6,720,433; U.S. Pat. Appl. Publ. 2003/176643; Intl. Pat. Appl. Publ. WO 99/09053; WO 00/17231; WO 00/44770; WO 02/64623). These peptidic antagonists suffer from the known limitations of peptides as drug molecules, in particular poor oral bioavailability and degradative metabolism.
Cyclization of peptidic derivatives is a method that can be employed to improve the properties of a linear peptide both with respect to metabolic stability and conformational freedom. Cyclic molecules tend to be more resistant to metabolic enzymes. Such cyclic peptide motilin antagonists have been reported, highlighted by GM-109. (Takanashi, H.; Yogo, K.; Ozaki, M.; Akima, M.; Koga, H.; Nabata, H. J. Pharm. Exp. Ther. 1995, 273, 624-628; Haramura, M.; Okamachi, A.; Tsuzuki, K.; Yogo, K.; Ikuta, M.; Kozono, T.; Takanashi, H.; Murayama, E. Chem. Pharm. Bull. 2001, 49, 40-43; Haramura, M.; Okamachi, A.; Tsuzuki, K.; Yogo, K.; Ikuta, M.; Kozono, T.; Takanashi, H.; Murayama, E. J. Med. Chem. 2002, 45, 670-675; U.S. Pat. No. 7,018,981; U.S. Pat. Appl. Publ. 2003/191053; Intl. Pat. Appl. Publ. WO 02/16404; Jap. Pat. Abstr. Publ. No. 07138284)
Macrocyclic peptidomimetics have been previously described as antagonists of the motilin receptor and their uses for the treatment of a variety of GI disorders and to modulate the migrating motor complex summarized. (Intl. Pat. Appl. Publ. WO 2004/111077; U.S. Pat. Appl. Publ. 2005/054562; U.S. Prov. Pat. Appl. Ser. No. 60/938,655; U.S. Prov. Pat. Appl. Ser. No. 60/939,280; Marsault, E.; Hoveyda, H. R.; Peterson, M. L.; Saint-Louis, C.; Landry, A.; Vézina, M.; Ouellet, L.; Wang, Z.; Ramaseshan, M.; Beaubien, S.; Benakli, K.; Beauchemin, S.; Déziel, R.; Peeters, T.; Fraser, G. L. J. Med. Chem. 2006, 49, 7190-7197; Marsault, E.; Benakli, K.; Beaubein, S.; Saint-Louis, C.; Déziel, R.; Fraser, G. Bioorg Med. Chem. Lett. 2007, 17, 4187-4190.) These peptidomimetic macrocyclic motilin antagonists are distinguished from the aforementioned cyclic peptide motilin antagonists in that it was found that such peptidic derivatives containing D-amino acids were devoid of activity. In contrast, for the tripeptidomimetic compounds of the present invention, the D-stereochemistry is beneficial for two of the three building elements. Further, the tether portion of the molecule provides a non-peptidic component and, hence, distinct structures.
The peptidomimetic macrocycles of the present invention are demonstrated to have binding and functional activity at the motilin receptor. Although binding potency and target affinity are factors in drug discovery and development, also important for development of viable pharmaceutical agents are optimization of pharmacokinetic (PK) and pharmacodynamic (PD) parameters. A focus area for research in the pharmaceutical industry has been to better understand the underlying factors which determine the suitability of molecules in this manner, often colloquially termed its “drug-likeness.” (Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev. 1997, 23, 3-25; Muegge, I. Med. Res. Rev. 2003, 23, 302-321; Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615-2623.) For example, molecular weight, log P, membrane permeability, the number of hydrogen bond donors and acceptors, total polar surface area (TPSA), and the number of rotatable bonds have all been correlated with compounds that have been successful in drug development. Additionally, experimental measurements of plasma protein binding, interaction with cytochrome P450 enzymes, and pharmacokinetic parameters are employed in the pharmaceutical industry to select and advance new drug candidates.
However, these parameters have not been widely explored or reported within the macrocyclic structural class. This creates tremendous challenges in drug development for such molecules. The macrocyclic compounds of the present invention have been found to possess desirable pharmacological characteristics, while maintaining sufficient binding affinity and selectivity for the motilin receptor, as illustrated in the Examples. These combined characteristics make them more suitable for development as pharmaceutical agents.
Other motilin antagonists, which are non-peptidic and non-macrocyclic in nature have also been reported. [(RWJ-68023: Beavers, M. P.; Gunnet, J. W.; Hageman, W.; Miller, W.; Moore, J. B.; Zhou, L.; Chen, R. H. K.; Xiang, A.; Urbanski, M.; Combs, D. W.; Mayo, K. H.; Demarest, K. T. Drug Design Disc. 2001, 17, 243-251); Johnson, S. G.; Gunnet, J. W.; Moore, J. B.; et al. Bioorg. Med. Chem. Lett. 2006, 16, 3362-3366; U.S. Pat. Nos. 5,972,939; 6,384,031; 6,392,040; 6,423,714; 6,511,980; 6,624,165; 6,667,309; 6,967,199; U.S. Pat. Appl. Publ. 2001/041701; 2001/056106, 2002/002192; 2002/013352; 2002/103238; 2002/111484; 2003/203906; 2005/148584; 2007/054888; Intl. Pat. Appl. Publ. WO 99/21846; WO 01/68620; WO 01/68621; WO 01/68622; WO 01/85694) Of these, RWJ-68023 has been examined in humans, but with a poor outcome, likely due to the level of potency of this molecule. (Kamerling, I. M. C.; van Haarst, A. D.; Burggraaf, J.; et al. Br. J. Clin. Pharmacol. 2003, 57, 393-401.)
Indeed, neither of the previously well-studied motilin antagonists, RWJ-68023 and GM-109, possessed the preferred full profile for a potential pharmaceutical product targeting this receptor including high binding affinity and functional activity at the motilin receptor, good Caco-2 membrane permeability, appropriate pharmacokinetic profile [reasonable plasma half-life (t1/2) and clearance values (ClT)], oral bioavailability, sufficient solubility to facilitate formulation and in vivo efficacy. In contrast, the macrocyclic motilin antagonists of the present invention have been found to possess at least some, if not all, of these favorable characteristics.